Role of the geneticist in testing and counseling for inherited thrombophilia

Within the past decade, the identification of two mutations that are relatively prevalent among the white population (the factor V Leiden and prothrombin G20210A gene mutations) has paved the way for a number of large cohort studies that have greatly advanced our understanding of the pathogenesis of venous thromboembolism (VTE). VTE is clearly a multigenic disorder, with well-characterized examples of gene-gene and gene-environment interactions underlying its pathogenesis. Increasing numbers of patients are being referred for testing, and many more diagnoses of inherited thrombophilia are being made. The purpose of this article is to discuss the practical applications of both diagnostic testing and genetic counseling for the major inherited thrombophilias: inherited resistance to activated protein C/factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency. A description of each entity is included along with a discussion of the indications for testing, selection of the most appropriate screening test, and proper interpretation of test results. Informed consent for testing, screening of asymptomatic individuals in special circumstances (such as during pregnancy or before initiation of estrogen therapy), screening of family members, and posttest education are also addressed. This article emphasizes that these polymorphisms should be regarded as risk factors for thrombosis whose clinical expression generally depends on the coexistence of additional thrombophilic mutations or environmental conditions that provoke the development of VTE.